BACKGROUND: To study the pharmacokinetic and -dynamic behavior of landiolol in the presence of dobutamine in healthy subjects of European ancestry. METHODS: We conducted a single-center, prospective randomized study in 16 healthy subjects each receiving an infusion of dobutamine sufficient to increase heart rate by 30 bpm followed by a 60 min infusion of 10 μg/kg/min landiolol. RESULTS: Dobutamine-induced increases in heart rate were stable for at least 20 min before a 60 min landiolol- infusion was started. The dobutamine effects were rapidly antagonized by landiolol within 16 min. A further slight decrease in heart rate during 20-60 min of the landiolol infusion occurred as well. Upon termination of landiolol infusion, heart rate and blood pressure recovered rapidly in response to the persisting dobutamine infusion but did not return to the maximum values before landiolol infusion. The pharmacokinetic parameters of landiolol in presence of dobutamine showed a short half-life (3.5 min) and a low distribution volume (0.3 l/kg). No serious adverse events were observed. CONCLUSION: Landiolol can antagonize the dobutamine-induced increases in heart rate and blood pressure in a fast way. A rapid bradycardic effect until steady-state plasma levels is followed by a slow heart rate reduction. The latter can be attributed to an early desensitization to dobutamine. Consequently, after termination of landiolol, the heart rate did not achieve maximum pre-landiolol values. The pharmacokinetics of landiolol during dobutamine infusion are similar when compared to short- and long-term data in Caucasian subjects. Landiolol in the given dose can thus serve as an antagonist of dobutamine-induced cardiac effects. TRIAL REGISTRATION: Registration number 2010-023311-34 at the EU Clinical Trials Register, registration date 2010-12-21.

• Keywords
• Cardioselective β-blocker, Dobutamine, Landiolol, Pharmacodynamics, Pharmacokinetics,
• MeSH
• Adrenergic beta-Antagonists administration & dosage   pharmacokinetics   MeSH
• Dobutamine administration & dosage   pharmacokinetics   MeSH
• Adult MeSH
• Double-Blind Method MeSH
• Infusions, Intravenous MeSH
• Cardiotonic Agents administration & dosage   pharmacokinetics   MeSH
• Cross-Over Studies MeSH
• Blood Pressure drug effects   physiology   MeSH
• Humans MeSH
• Young Adult MeSH
• Urea administration & dosage   analogs & derivatives   pharmacokinetics   MeSH
• Morpholines administration & dosage   pharmacokinetics   MeSH
• Prospective Studies MeSH
• Heart Rate drug effects   physiology   MeSH
• Healthy Volunteers MeSH
• Check Tag
• Adult MeSH
• Humans MeSH
• Young Adult MeSH
• Male MeSH
• Female MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Randomized Controlled Trial MeSH
• Names of Substances
• Adrenergic beta-Antagonists MeSH
• Dobutamine MeSH
• Cardiotonic Agents MeSH
• landiolol MeSH Browser
• Urea MeSH
• Morpholines MeSH

BACKGROUND: In patients with septic shock, the presence of an elevated heart rate (HR) after fluid resuscitation marks a subgroup of patients with a particularly poor prognosis. Several studies have shown that HR control in this population is safe and can potentially improve outcomes. However, all were conducted in a single-center setting. The aim of this multicenter study is to demonstrate that administration of the highly beta1-selective and ultrashort-acting beta blocker landiolol in patients with septic shock and persistent tachycardia (HR ≥ 95 beats per minute [bpm]) is effective in reducing and maintaining HR without increasing vasopressor requirements. METHODS: A phase IV, multicenter, prospective, randomized, open-label, controlled study is being conducted. The study will enroll a total of 200 patients with septic shock as defined by The Third International Consensus Definitions for Sepsis and Septic Shock criteria and tachycardia (HR ≥ 95 bpm) despite a hemodynamic optimization period of 24-36 h. Patients are randomized (1:1) to receive either standard treatment (according to the Surviving Sepsis Campaign Guidelines 2016) and continuous landiolol infusion to reach a target HR of 80-94 bpm or standard treatment alone. The primary endpoint is HR response (HR 80-94 bpm), the maintenance thereof, and the absence of increased vasopressor requirements during the first 24 h after initiating treatment. DISCUSSION: Despite recent studies, the role of beta blockers in the treatment of patients with septic shock remains unclear. This study will investigate whether HR control using landiolol is safe, feasible, and effective, and further enhance the understanding of beta blockade in patients with septic shock. TRIAL REGISTRATION: EU Clinical Trials Register; EudraCT, 2017-002138-22 . Registered on 8 August 2017.

• Keywords
• Beta-blocker, Landiolol, Randomized controlled trial, Sepsis, Septic shock, Tachycardia,
• MeSH
• Anti-Arrhythmia Agents adverse effects   therapeutic use   MeSH
• Adrenergic beta-Antagonists adverse effects   therapeutic use   MeSH
• Time Factors MeSH
• Intensive Care Units * MeSH
• Clinical Trials, Phase IV as Topic MeSH
• Blood Pressure drug effects   MeSH
• Humans MeSH
• Urea adverse effects   analogs & derivatives   therapeutic use   MeSH
• Morpholines adverse effects   therapeutic use   MeSH
• Multicenter Studies as Topic MeSH
• Prospective Studies MeSH
• Randomized Controlled Trials as Topic MeSH
• Shock, Septic diagnosis   drug therapy   physiopathology   MeSH
• Heart Rate drug effects   MeSH
• Vasoconstrictor Agents therapeutic use   MeSH
• Treatment Outcome MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH
• Clinical Trial Protocol MeSH
• Geographicals
• Europe MeSH
• Names of Substances
• Anti-Arrhythmia Agents MeSH
• Adrenergic beta-Antagonists MeSH
• landiolol MeSH Browser
• Urea MeSH
• Morpholines MeSH
• Vasoconstrictor Agents MeSH

PURPOSE: The aim of this prospective study was to compare in non-Asian subjects the pharmacokinetics (PK), pharmacodynamics (PD), safety, and tolerability of two short-acting cardioselective β1-adrenergic antagonists, landiolol and esmolol, after administration of three different bolus dosages. MATERIALS AND METHODS: We conducted a single-center, prospective, double-blinded, randomized study in three cross-over periods with 12 healthy subjects (7 women and 5 men, mean age of 24.5 ± 6.9 years) each receiving three doses of landiolol (0.1, 0.2, and 0.3 mg/kg BW) either in a newly developed concentrate i.v. formulation (Rapibloc® 20 mg/2 mL concentrate) or a lyophilized formulation, or three doses of esmolol (0.5, 1, and 1.5 mg/kg BW) in an i.v. formulation (Brevibloc® 100 mg/10 mL). PK and PD parameters, safety, and tolerability were assessed. FINDINGS: Results of the two landiolol formulations were reported previously and were similar. For the landiolol concentrate formulation and esmolol, maximum blood concentrations were rapidly reached (mean t max ranged between 1.8 and 3.0 min for landiolol and 1.8 to 2.4 min for esmolol). The parent drugs disappeared very fast from the blood stream, with a t 1/2 of 3.2 ± 1.2 (SD) minutes and 3.7 ± 2.1 (SD) minutes for the low doses of landiolol and esmolol, respectively. Despite comparable injection rates (0.1 or 0.5 mg/kg/15 s for landiolol and esmolol, respectively), the onset of significant heart rate reduction occurred earlier in response to landiolol (1 min) than in response to esmolol (2 min). In addition, significantly lower heart rate values were obtained at every dose level of landiolol, in comparison to esmolol (p < 0.05). Both compounds reduced the systolic blood pressure to a comparable degree. Especially at the highest dose, the duration of blood pressure reduction was longer under esmolol compared to landiolol. Seven mild to moderate adverse events occurred after administration of landiolol, and five occurred after administration of esmolol. No serious adverse events were reported in this study. IMPLICATIONS: Heart rate reduction induced by a new liquid formulation of landiolol occurred faster, was more pronounced, and lasted longer than the effects of corresponding standard esmolol doses. Both agents reduced systolic blood pressure to a comparable degree, but the blood pressure decrease lasted longer after esmolol infusion. The local tolerance and safety profiles of the two formulations were similar. In summary, compared to esmolol, landiolol shows a more prominent and pronounced bradycardic effect in relation to its blood pressure-lowering effect, an action profile that might be of specific advantage in the perioperative setting. TRIAL REGISTRATION: NCT01652898 and 2012-002127-14. https://clinicaltrials.gov/ct2/show/NCT01652898?term=landiolol&rank=7.

• Keywords
• Cardioselective β-blocker, Esmolol, Landiolol, Pharmacodynamics, Pharmacokinetics,
• MeSH
• White People * MeSH
• Adrenergic beta-Antagonists administration & dosage   pharmacokinetics   pharmacology   MeSH
• Adult MeSH
• Double-Blind Method MeSH
• Humans MeSH
• Young Adult MeSH
• Urea administration & dosage   analogs & derivatives   pharmacokinetics   pharmacology   MeSH
• Morpholines administration & dosage   pharmacokinetics   pharmacology   MeSH
• Propanolamines administration & dosage   pharmacokinetics   pharmacology   MeSH
• Prospective Studies MeSH
• Check Tag
• Adult MeSH
• Humans MeSH
• Young Adult MeSH
• Male MeSH
• Female MeSH
• Publication type
• Journal Article MeSH
• Randomized Controlled Trial MeSH
• Comparative Study MeSH
• Names of Substances
• Adrenergic beta-Antagonists MeSH
• esmolol MeSH Browser
• landiolol MeSH Browser
• Urea MeSH
• Morpholines MeSH
• Propanolamines MeSH